Methods for treating severe acute respiratory syndrome

ABSTRACT

The invention provides methods for treating severe acute respiratory syndrome (SARS) with lipopolysaccharides.

RELATED APPLICATION

This application is a continuation of PCT/US2004/022123 filed Jul. 12,2004, which claims priority to U.S. Application No. 60/486,444 filedJul. 14, 2003, the disclosures of which are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

The invention provides methods for treating severe acute respiratorysyndrome with lipopolysaccharides.

BACKGROUND OF THE INVENTION

Severe acute respiratory syndrome (SARS) is a respiratory illness thathas recently been reported in Asia, North America, and Europe. Patientswith severe acute respiratory syndrome generally experience one or moresymptoms that include a fever greater than 100° F., headaches, malaise,and body aches. Some patients also experience mild respiratory symptoms.After 2 to 7 days, patients may develop a dry cough and have troublebreathing.

Severe acute respiratory syndrome may be spread by person-to-personcontact. Most cases of severe acute respiratory syndrome have involvedpeople who cared for or lived with someone with the disease, or haddirect contact with infectious material (e.g., respiratory secretions)from a patient. Severe acute respiratory distress syndrome can be spreadby touching the skin of people or objects that are contaminated withinfectious droplets. It is possible that severe acute respiratorysyndrome can be spread more broadly through the air or by other waysthat are currently not known.

There is a need in the art for therapeutic treatments for severe acuterespiratory syndrome. The invention is directed to this, as well asother, important ends.

SUMMARY OF THE INVENTION

The invention provides methods for treating severe acute respiratorysyndrome by administering to a patient in need thereof a therapeuticallyeffective amount of at least one lipopolysaccharide. The invention alsoprovides methods for treating sepsis caused by severe acute respiratorysyndrome by administering to a patient in need thereof a therapeuticallyeffective amount of at least one lipopolysaccharide.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods for treating or preventing severe acuterespiratory syndrome by administering to a patient in need thereof atherapeutically effective amount of at least one lipopolysaccharide. Inone embodiment, the invention provides methods for treating orpreventing sepsis caused by severe acute respiratory syndrome in apatient in need thereof by administering a therapeutically effectiveamount of at least one lipopolysaccharide.

Exemplary lipopolysaccharides include the compounds described in WO96/39411 and U.S. Pat. Nos. 5,530,113, 5,681,824, 5,750,664, 5,935,938,6,184,366 and 6,417,172, the disclosures of which are incorporated byreference herein in their entirety. These compounds are generallyrepresented by Formula (A), pharmaceutically acceptable salts thereof,and/or stereoisomers (including enantiomers and/or diastereomers)thereof:

wherein R¹ is selected from the group consisting of:

J, K and Q are each independently a straight or branched C₁₋₁₅ alkyl;

L is O, N or C;

M is O or N;

G is N, O, S, SO or SO₂;

R² is a straight or branched C₅₋₁₅ alkyl;

R³ is selected from the group consisting of:

E is N, O, S, SO or SO₂;

A, B and D are each independently a straight or branched C₁₋₁₅ alkylgroup;

R⁴ is a straight or branched C₄₋₂₀ alkyl group or

U and V are each independently a straight or branched C₂₋₁₅ alkyl group;

W is a hydrogen or a straight or branched C₁₋₅ alkyl group;

R⁵ is hydrogen, -J′, -J′-OH, -J′-O—K′, -J′-O—K′—OH or J′-O—PO(OH)₂;

J′ and K′ are each independently a straight or branched C₁₋₅ alkylgroup;

R⁶ is hydroxy, halogen, a C₁₋₅ alkoxy group or a C₁₋₅ acyloxy group;

A¹ and A² are each independently selected from the group consisting of:

Z is a straight or branched C₁₋₁₀ alkyl group.

The term “alkyl” refers to aliphatic organic groups which may bebranched or straight and which may optionally be substituted with one ormore halogen atoms at any position along the alkyl chain. The term“pharmaceutically acceptable salt” includes salts of compounds derivedfrom the combination of the compound and an organic or inorganic acid orbase.

A preferred compound of Formula (A) is Compound (1), pharmaceuticallyacceptable salts thereof, and/or stereoisomers (including enantiomersand/or diastereomers) thereof:

In a preferred embodiment, Compound (1) is Compound (1A) or apharmaceutically acceptable salt thereof, which is represented by thefollowing formula:

When Compound 1A is a sodium salt (i.e., one or both hydrogen atoms inthe —OPO(OH)₂ groups are replaced with sodium), then the compound isE5564.

Other preferred compounds described in WO 96/39411 and U.S. Pat. Nos.5,530,113, 5,681,824, 5,750,664, 5,935,938, and 6,184,366 for use in thepresent invention include those of Formula (B), pharmaceuticallyacceptable salts thereof, and/or stereoisomers (including enantiomersand/or diastereomers) thereof:

wherein R¹, R³ and R⁴ are as defined below: # R¹ R³ R⁴ 1COCH₂CO(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OCH₃)(CH₂)₆CH₃ 2COCH₂CO(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 3COCH₂CO(CH₂)₁₀CH₃ CO(CH₂)₁₆CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 4COCH₂CHOH(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 5COCH₂CO(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₉CH₃ 6CO(CH₂)₉CH═CH(CH₂)₅CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 7CO(CH₂)₁₂CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 8COCH₂CH(OCH₃)(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OCH₃)(CH₂)₆CH₃ 9COCH₂CH(OCH₃)(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OH)(CH₂)₆CH₃ 10COCH₂CH(OH)(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OCH₃)(CH₂)₆CH₃ 11COCH₂CO(CH₂)₁₀CH₃ CO(CH₂)₉CH═CH(CH₂)₅CH₃ (CH₂)₂CH(OCH₃)(CH₂)₆CH₃wherein R_(A) in Compounds (1)-(10) is CH₂OCH₃ and R_(A) in Compound(11) is CH₃.

Methods for making Compounds (1) and (1A) and the compounds of Formulas(A) and (B) are described in WO 96/39411 and U.S. Pat. Nos. 5,530,113,5,681,824, 5,750,664, 5,935,938, 6,184,366, and 6,417,172, thedisclosures of which are incorporated by reference herein in theirentirety.

The compounds described herein and in WO 96/39411 and U.S. Pat. Nos.5,530,113, 5,681,824, 5,750,664, 5,935,938, 6,184,366, and 6,417,172 areadministered in dosages which provide a therapeutically effectivetreatment for severe acute respiratory syndrome; generally, thesedosages are between about 0.01 and about 500 mg/patient, between about0.05 and about 100 mg/patient; between about 1 and about 50 mg/patient;between about 1 and about 25 mg/patient; or between about 1 and about 12mg/patient. The dosages can be administered over three to six days as acontinuous infusion or as an intermittent dosing to obtain desiredplasma concentrations. It will be understood, however, that the specificdose level for any particular patient will depend on a variety offactors including the activity of the specific compound used; the age,weight, general health, and sex of the patient being treated; the timeand route of administration; the rate of excretion; and other drugswhich have previously been administered.

Pharmaceutical compositions containing the active ingredient may be inany form suitable for the intended method of administration. Aqueoussolutions and/or suspensions of the invention contain thelipopolysaccharides in admixture with excipients suitable for themanufacture thereof. Such excipients include a suspending agent, such assodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gumacacia, and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadeaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservative such as ethyl of n-propylp-hydroxybenzoate.

The pharmaceutical compositions of the invention are preferably in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render theformation isotonic with the blood of the intended recipient; and aqueousand non-aqueous sterile suspensions which may include suspending agentsand thickening agents. The formulations may be presented in unit-dose ormulti-dose sealed containers, for example, ampules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water forinjections, immediately prior to use. Extemporaneous injection solutionsand suspensions may be prepared from sterile powders of the kindpreviously described.

When using a lyophilized drug product, clinicians typically reconstitutethe freeze-dried preparation in physiologically acceptable solutions. Itis desirable to be able to store the reconstituted solution either atroom temperature or under refrigeration. Freeze-dried preparations arerehydratable with water or an aqueous dextrose solution suitable forintravenous administration. Such reconstituted solutions can be storedat room temperature or refrigerated temperatures.

Each of the patents and publications cited herein are incorporated byreference herein in their entirety.

It will be apparent to one skilled in the art that various modificationscan be made to the invention without departing from the spirit or scopeof the appended claims.

1. A method for treating severe acute respiratory syndrome in a patientin need thereof comprising administering a therapeutically effectiveamount of a compound of Formula (1A) or a pharmaceutically acceptablesalt thereof:


2. The method of claim 1, wherein the compound of Formula (1A) is in theform of a sodium salt.
 3. The method of claim 1, wherein the compound ofFormula (1A) or the pharmaceutically acceptable salt thereof isadministered to the patient in an amount from 0.01 mg to 500 mg.
 4. Themethod of claim 1, wherein the compound of Formula (1A) or thepharmaceutically acceptable salt thereof is administered to the patientin an amount from 1 mg to 50 mg.
 5. The method of claim 1, wherein thecompound of Formula (1A) or the pharmaceutically acceptable salt thereofis parenterally administered to the patient.
 6. A method for treatingsevere acute respiratory syndrome in a patient in need thereofcomprising administering a therapeutically effective amount of acompound of Formula (A) or a pharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of:

J, K and Q are each independently a straight or branched C₁₋₅ alkyl; Lis O, N or C; M is Q or N; G is N, O, S, SO or SO₂; R² is a straight orbranched C₅₋₁₅ alkyl; R³ is selected from the group consisting of:

E is N, O, S, SO or SO₂; A, B and D are each independently a straight orbranched C₁₋₁₅ alkyl group; R⁴ is a straight or branched C₄₋₂₀ alkylgroup or

U and V are each independently a straight or branched C₂₋₁₅ alkyl group;W is a hydrogen or a straight or branched C₁₋₅ alkyl group; R⁵ ishydrogen, -J′, -J′-OH, -J′-O—K′, -J′-O—K′—OH or J′-O—PO(OH)₂; J′ and K′are each independently a straight or branched C₁₋₅ alkyl group; R⁶ ishydroxy, halogen, a C₁₋₅ alkoxy group or a C₁₋₅ acyloxy group; A¹ and A²are each independently selected from the group consisting of:

Z is a straight or branched C₁₋₁₀ alkyl group.
 7. The method of claim 6,wherein the compound of Formula (A) or the pharmaceutically acceptablesalt thereof is administered to the patient in an amount from 0.01 mg to500 mg.
 8. The method of claim 6, wherein the compound of Formula (A) orthe pharmaceutically acceptable salt thereof is administered to thepatient in an amount from 1 mg to 50 mg.
 9. The method of claim 6,wherein the compound of Formula (A) or the pharmaceutically acceptablesalt thereof is parenterally administered to the patient.
 10. The methodof claim 2, wherein the compound of Formula (A) is a compound of Formula(B) or a pharmaceutically acceptable salt thereof:

wherein R_(A), R¹, R³ and R⁴ are as defined for the compound of Formula(A).
 11. A method for treating sepsis caused by severe acute respiratorysyndrome in a patient in need thereof comprising administering atherapeutically effective amount of a compound of Formula (A) or apharmaceutically acceptable salt thereof:

wherein R¹ is selected from the group consisting of:

J, K and Q are each independently a straight or branched C₁₋₁₅ alkyl; Lis O, N or C; M is O or N; G is N, O, S, SO or SO₂; R² is a straight orbranched C₅₋₁₅ alkyl; R³ is selected from the group consisting of:

E is N, O, S, SO or SO₂; A, B and D are each independently a straight orbranched C₁₋₁₅ alkyl group; R⁴ is a straight or branched C₄₋₂₀ alkylgroup or

U and V are each independently a straight or branched C₂₋₁₅ alkyl group;W is a hydrogen or a straight or branched C₁₋₅ alkyl group; R⁵ ishydrogen, -J′, -J′-OH, -J′-O—K′, -J′-O—K′—OH or J′-O—PO(OH)₂; J′ and K′are each independently a straight or branched C₁₋₅ alkyl group; R⁶ ishydroxy, halogen, a C₁₋₅ alkoxy group or a C₁₋₅ acyloxy group; A¹ and A²are each independently selected from the group consisting of:

Z is a straight or branched C₁₋₁₀ alkyl group.
 12. The method of claim11, wherein the compound of Formula (A) or the pharmaceuticallyacceptable salt thereof is administered to the patient in an amount from0.01 mg to 500 mg.
 13. The method of claim 11, wherein the compound ofFormula (A) or the pharmaceutically acceptable salt thereof isadministered to the patient in an amount from 1 mg to 50 mg.
 14. Themethod of claim 11, wherein the compound of Formula (A) or thepharmaceutically acceptable salt thereof is parenterally administered tothe patient.
 15. The method of claim 11, wherein the compound of Formula(A) is a compound of Formula (B) or a pharmaceutically acceptable saltthereof:

wherein R_(A), R¹, R³ and R⁴ are as defined for the compound of Formula(A).
 16. The method of claim 11, wherein the compound of Formula (A) isa compound of Formula (1) or a pharmaceutically acceptable salt thereof:


17. The method of claim 11, wherein the compound of Formula (A) is acompound of Formula (1A) or a pharmaceutically acceptable salt thereof:


18. The method of claim 17, wherein the compound of Formula (1A) is inthe form of a sodium salt.
 19. The method of claim 17, wherein thecompound of Formula (1A) or the pharmaceutically acceptable salt thereofis administered to the patient in an amount from 0.01 mg to 500 mg. 20.The method of claim 17, wherein the compound of Formula (1A) or thepharmaceutically acceptable salt thereof is parenterally administered tothe patient.